Nitric oxide (NO) has long been established as a signaling molecule that promotes relaxation of smooth muscle cells. More recently, it has been established that NO can mediate other biological processes and diseases including, for example, wound healing, inflammation, plant disease resistance, sexual dysfunction, social dysfunction, cancer, coronary heart disease, restenosis, hypertension and angiogensis. The implication of NO in so many biological processes and diseases has stimulated interest in its exogenous delivery. However, NO is a diatomic free radical, and its exogenous delivery as a gas to biological systems has proved impractical due to its high reactivity.
A number of systems have been proposed and tested for in situ generation and delivery of NO. Such systems include chemical compounds such as, for example, diazeniumdiolates and S-nitrosothiols. Other examples include, NO-releasing gold nanoparticles, NO-releasing polyethyleneimine (PEI) fibers and NO-releasing zeolites. Diazeniumdiolates and zeolites are materials that hold particular promise for in situ generation of NO. However, neither of these systems has yet been successfully implemented in a controlled-release formulation that provides a sustained generation of NO over an extended period. Further, efforts to formulate diazeniumdiolates within a polymer matrix have been hampered by leaching of these hydrophilic molecules from the matrix. Leached diazeniumdiolates may become toxic in vivo due to metabolic conversion to N-nitrosamines, which are potentially carcinogenic materials.
Zeolites are open, stable, three-dimensional microporous aluminosilicates composed of ordered tetrahedra of AlO4 and SiO4. These materials have experienced a growing interest for biomedical applications. Zeolites are the aluminosilicate members of the family of microporous solids known as “molecular sieves.” With regard to in situ delivery of NO, they have shown exceptional promise for their ability to store and reversibly release NO from their microporous structure. In spite of their ability to readily store NO, application of NO-loaded zeolites and other porous materials as a free powder to biological systems is generally not considered practical.
In view of the foregoing, new biocompatible systems for controlled or sustained release of NO would be of substantial benefit. Desirably, such systems would promote controlled or sustained release of NO to exploit the desirable properties of NO in biological systems, while at the same time minimizing the toxicity or biological incompatibility of the NO-releasing material. Biocompatible systems for controlled or sustained release of NO may be incorporated into medical devices as described herein.